Isotopically labeled compositions and method

ABSTRACT

Compounds having stable isotopes  13 C and/or  2 H were synthesized from precursor compositions having solid phase supports or affinity tags.

STATEMENT REGARDING FEDERAL RIGHTS

This invention was made with government support under Contract No.DE-AC52-06NA25396 awarded by the U.S. Department of Energy. Thegovernment has certain rights in the invention.

FIELD OF THE INVENTION

The present invention relates generally to compositions and methods forsynthesizing compounds labeled with stable isotopes.

BACKGROUND OF THE INVENTION

Isotopically labeled molecules are used for structural and mechanisticstudies of important chemical and biological processes. Isotopicallylabeled amino acids and nucleotides, for example, are used forstructural and mechanistic studies of proteins and oligonucleotides.Isotopically labeled biologically active compounds, for example, areused for many phases of drug discovery and development includingelucidation of biosynthetic pathways, pharmacokinetics, and drugmetabolism. Compounds can be isotopically enriched with a radioactivelabel or with a nonradioactive label. Non-radioactive isotopes (i.e.stable isotopes) can be used to avoid subsequent disposal of radioactivewaste.

Compounds labeled with stable isotopes such as carbon-13 (¹³C) anddeuterium (2H) typically are synthesized using solution-based methods(see, for example: U.S. Pat. No. 6,730,805 to Martinez et al. entitled“Synthesis of ²H- and ¹³C-Substituted Compounds”; U.S. Pat. No.6,541,671 to Martinez et al. entitled “Synthesis of [²H₁, ¹³C], [²H₂,¹³C] and [2H₃, ¹³C]Methyl Aryl Sulfides”; U.S. Pat. No. 6,713,044 toMartinez entitled “Synthesis of [²H₁, ¹³C], [²H₂, ¹³C] and [²H₃,¹³C]Methyl Aryl Sulfides”; U.S. Pat. No. 6,764,673 to Martinez et al.entitled “Synthesis of [²H₁, ¹³C], [²H₂, ¹³C] and [²H₃, ¹³C]Methyl ArylSulfones and Sulfoxides”; U.S. Pat. No. 6,764,673; and U.S. Pat. No.6,753,446 to Martinez et al. entitled “Synthesis of Labeled Oxalic AcidDerivatives,” all incorporated by reference herein).

Typical solution phase methods often result in product mixtures thatdecrease the overall yield of a desired isotopically labeled material.In addition, laborious separation and purification steps may also beneeded to isolate the desired labeled material and these steps add tothe cost and inefficiency of a synthesis of a desired isotopicallylabeled material.

The remains a need for better methods for synthesizing isotopicallylabeled compounds, and for compositions that can be easily converted toisotopically labeled compounds.

SUMMARY OF THE INVENTION

In accordance with the purposes of the present invention, as embodiedand broadly described herein, the present invention includes acomposition having the formula

A-D-E-C(TXZ)

wherein A includes a support or an affinity tag;

wherein D includes an aryl group;

wherein E includes a group chosen from sulfur, sulfoxide, sulfone,selenium, selenoxide, and selenone;

wherein T, X, and Z include groups each independently chosen from ¹H,²H, a C₁-C₄ alkyl, fluoro, chloro, bromo, iodo, amino, NHR, NR₂, and OR;

wherein R includes a group chosen from a C₁-C₄ alkyl, chloro, bromo,amino, monocyclic aryl, substituted monocyclic aryl, bicyclic aryl, andsubstituted bicyclic aryl; and

wherein at least one of C, T, X, and Z groups includes a stable isotope,wherein the stable isotope of C is ¹³C and wherein the stable isotope ofT, X, Z is chosen from ¹³C and ²H.

The invention also includes a composition having the formula

or of the formula

or of the formula

or of the formula

wherein each G group is independently chosen from a support, hydrogen, aC₁-C₄ alkyl, haloalkyl, cycloalkyl, cyano, fluoro, chloro, bromo, iodo,NH₂, NHR, NR₂, —OM, OR, and —COOQ;

wherein at least one G group is a support;

wherein M is chosen from hydrogen, alkyl, haloalkyl, cycloalkyl, phenyl,and substituted phenyl;

wherein Q is chosen from hydrogen and alkyl;

wherein E comprises a group chosen from sulfur, sulfoxide, sulfone,selenium, selenoxide, and selenone;

wherein T, X, and Z are groups each independently chosen from ¹H, ²H, aC₁-C₄ alkyl, fluoro, chloro, bromo, iodo, amino, NHR, NR₂, and OR;

wherein R is chosen from a C₁-C₄ alkyl, chloro, bromo, amino, amonocyclic aryl, substituted monocyclic aryl, bicyclic aryl, andsubstituted bicyclic aryl;

wherein R_(f) is a fluorous group;

wherein each J is independently selected from hydrogen and alkyl,wherein m is 2, 3, 4, 5, or 6; and

wherein at least one of C, T, X, and Z comprises a stable isotope,

wherein the stable isotope of C is ¹³C and wherein the stable isotope ofT, X, Z comprises ¹³C or ²H.

The invention also includes a method for synthesizing an isotopicallyenriched compound. The method involves forming a composition having theformula

A-D-E-C(TXZ)

wherein A includes a support or affinity tag; wherein D includes an arylgroup; wherein E includes a group chosen from sulfur, sulfoxide,sulfone, selenium, selenoxide, and selenone; wherein T, X, and Z includegroups each independently chosen from ¹H, ²H, a C₁-C₄ alkyl, fluoro,chloro, bromo, iodo, amino, NHR, NR₂, and OR; wherein R includes a groupchosen from a C₁-C₄ alkyl, chloro, bromo, amino, monocyclic aryl,substituted monocyclic aryl, bicyclic aryl, and substituted bicyclicaryl; wherein at least one of C, T, X, and Z groups comprises a stableisotope, wherein the stable isotope of C is ¹³C, wherein the stableisotope of T, X, Z is chosen from ¹³C or ²H;

and subjecting the composition to conditions whereby —C(TXZ) detachesfrom E and becomes part of an isotopically labeled compound.

DETAILED DESCRIPTION

An aspect of the invention is concerned with compositions having a solidphase support that are useful for synthesizing compounds that areisotopically labeled with ¹³C, ²H, or both ¹³C and ²H.

Another aspect of the invention is concerned with synthesizingisotopically labeled compounds from compositions having a solid phasesupport. Separation and purification steps are minimized when a solidphase support is used because the desired isotopically labeled producttends to be a single labeled compound rather than a mixture of labeledcompounds. In addition, the yield of the desired isotopically labeledcompound tends to be at least as good as, and sometimes better than, theyield obtained when a solution-based method is used to synthesize thesame isotopically labeled compound.

In some embodiments, a precursor for making an isotopically labeledcompound was prepared by reacting a thiophenol resin with an excess ofisotopically labeled reagent; the excess drove the reaction tocompletion. During the reaction, an isotopically labeled portion fromthe reagent became attached to the resin. This precursor can be furthermodified by appropriate chemical reactions before detachment from theresin, yielding the desired isotopically labeled compound and a resinbyproduct that can be recovered and reused. Excess amounts ofisotopically labeled reagent can also be recovered relatively easilywhen the work-up involves only filtration of the product resin andremoval of solvents.

Other aspects of the invention are concerned with isotopically labeledcompositions having affinity tags, and with the preparation ofisotopically labeled compounds from these compositions. Affinity tagsinclude fluorous groups (—C₈F₁₇, for example) that facilitatepurification through a separation technique known in the art as fluoroussolid phase extraction (see, for example: Zhang et al., “SyntheticApplications of Fluorous Solid-Phase Extraction (F-SPE),” Tetrahedron,vol. 62 (2006), pp. 11837-11865, incorporated by reference herein).

The term “fluorous” refers generally to an organic molecule, or portionof a molecule, or group that is rich in carbon-fluorine bonds. Afluorohydrocarbon is an organic compound in which at least one hydrogenatom bonded to a carbon atom has been replaced with a fluorine atom. Afew examples of suitable fluorous groups for use in the presentinvention include, but are not limited to, —C₄F₉, —C₆F₁₃, —C₈F₁₇,—C₁₀F₂₁, —C(CF₃)₂C₃F₇, —C₄F₈CF(CF₃)₂, and —CF₂CF₂OCF₂CF₂OCF₃.

An embodiment of fluorous solid phase extraction (F—SPE) referred to inthe art as “standard F—SPE” employs fluorous silica gel, which is madeof silica gel bonded to a fluorocarbon phase such as—Si(CH₃)₂(CH₂)₂C₈F₁₇. This material is commercially available fromFLUOROUS TECHNOLOGIES, INC. under the trade name of FLUOROFLASH®.Briefly, a crude reaction mixture containing both fluorous andnon-fluorous reaction components is charged onto fluorous silica gel andthen the fluorous silica gel is eluted with a fluorophobic solvent suchas 70-80 percent methanol:H₂O, 50-60 percent CH₃CN:H₂O, 80-90 percentDMF:H₂O, or 100 percent DMSO. In this fluorophobic pass, non-fluorousorganic compounds typically move at or near the solvent front and elutefirst, while fluorous compounds are retained on the fluorous silica gel.In the subsequent fluorophilic pass, elution with one of many organicsolvents such as water-free methanol or acetonitrile, tetrahydrofuran,among others, then provides a fluorous fraction containing thosecompounds bearing the fluorous tag.

Alternatively, the philicities of the solid phase and the liquid phasemay be reversed, wherein standard silica gel is used as the polar solidphase while blends of fluorous and organic solvents are used as thefluorophilic liquid phase. This alternate separation is sometimesreferred to as “reverse F—SPE”.

The progress of a synthesis of an isotopically labeled compound can bemonitored easily by nuclear magnetic resonance (NMR) spectroscopy. Whenthe label is ¹³C, a carbon NMR spectrum of a reaction mixture may beobtained as the reaction proceeds. Analysis of the NMR spectrum providesan indication of the completeness of reaction.

In an embodiment, standard F—SPE was used to prepare an isotopicallylabeled composition (see EXAMPLES 15 and 16, infra).

Embodiment compositions include those of the formula

A-D-E-C(TXZ).

In the above formula, “A” symbolizes a chemical support or an affinitytag. Some non-limiting examples of chemical supports include apolyfluoroalkyl support, an aryl support, a metal support, ananoparticle support, a magnetic bead support, a silica support, apolymer support, a resin support, a silicon support, a glass support, aceramic support, and a core-shell material support. A non-limitingexample of a metal particle is a gold particle. A non-limiting exampleof a resin is polystyrene. Some non-limiting examples of polymersinclude polystyrene, TENTAGEL®, polyethylene glycol, polyethylene glycolsubstituted with vinyl benzene, and resin-bound thiophenol crosslinkedwith divinylbenzene. A non-limiting example of a nanoparticle support isgold nanoparticles. Some non-limiting examples of magnetic bead supportsinclude ferromagnetic beads, CoSm magnetic beads, and DYNAL® magneticbeads. Magnetic bead supports may be coated with a ceramic material,such as mesoporous silica. Some non-limiting examples of glass supportsinclude those commonly used in the synthesis of DNA. Glass beads may ormay not be derivatised with other materials. Some non-limiting examplesof ceramic supports include supports of silica or alumina. Somenon-limiting examples of core-shell materials are gold nanoparticles ofthe type disclosed in U.S. Patent Application 20050025969 entitled“Gold-Coated Nanoparticles for Use in Biomedical Applications,”incorporated by reference herein. Some non-limiting examples of affinitytags include those of the formula C₆F₁₃(CH₂)₃—, C₈F₁₇(CH₂)₃—,C₈F₁₇(CH₂)₂C(CH₃)₂—, and C₁₀F₂₁(CH₂)₃—.

In the above formula, “D” symbolizes an aryl group. It should beunderstood that aryl is meant to include monocyclic aromatic andpolycyclic aromatic groups such as, but not limited to, monocyclic aryl,monocyclic aryloxy (para-O—C₆H₄—, for example), substituted monocyclicaryl, substituted monocyclic aryloxy, bicyclic aryl, bicyclic aryloxy,substituted bicyclic aryl, and substituted bicyclic aryloxy. In someembodiments, when aryl is monocyclic aryloxy or bicyclic aryloxy, groupA may be connected to group D by oxygen of the aryloxy group. When arylgroup “D” is a six-membered aromatic ring, the substitution pattern of“A” and “E” may be ortho (i.e. 1,2-), meta (i.e. 1,3-), or para (i.e.1,4-). Aryl group “D” may be substituted in any and all positions in thering that are not already occupied by group “A” and group “E”. Somenon-limiting substituents on aryl group “D” include methyl, ethyl,propyl, isopropyl, butyl, isobutyl, t-butyl, alkenyl, chloro, bromo,haloalkyl, cycloalkyl, amino, alkylamino, dialkylamino, alkoxy, andaryloxy. Some non-limiting examples of haloalkyl substituents includechloromethyl, bromoethyl, fluoroisopropyl, and iodicyclopentyl.

In the above formula, Group “E” is a chemical group that connects arylgroup “D” to —C(X)(T)(Z). Group “E” can be one or more sulfur atoms(—S—, —S—S—, —S—S—S—, for example), one or more selenium atoms (-Se-,-Se-Se-, -Se-Se-Se, for example), a sulfoxide (—S(═O)—) group, a sulfonegroup (—S(═O)₂—), a selenoxide group (-Se(═O)—) or a selenone group(-Se(═O)₂—). If “E” is a sulfoxide group, stereoisomerism is possible atthe sulfur atom because the sulfur atom of a sulfoxide group is a chiralcenter.

The chemical groups symbolized by T, X, and Z can each be independentlyselected from ¹H, ²H, a C₁-C₄ alkyl, fluoro, chloro, bromo, iodo, amino,NHR, NR₂, alkoxy, and aryloxy. Alkoxy is symbolized as OR where the O isoxygen and the R is a group that can be, for example, a C₁-C₄ alkyl,monocyclic aryl, substituted monocyclic aryl, bicyclic aryl, andsubstituted bicyclic aryl.

It should also be understood that the composition of the formula

A-D-E-C(TXZ)

must include at least one stable isotope in the “C” group and/or in atleast one of the groups symbolized by T, X, and Z. In some embodiments,C is isotopically enriched with ¹³C while none of T, X, and Z include anisotopically enriched isotope. In embodiments, C is not isotopicallyenriched with ¹³C but one, two, or all three of T, X, and Z includeisotopically enriched groups. In yet other embodiments, C is enriched in¹³C and one, two, or three of T, X, and Z groups are isotopicallyenriched in ¹³C and/or ²H.

An embodiment composition having a support is of the formula

wherein each G group is independently chosen from a support, hydrogen, aC₁-C₄ alkyl, haloalkyl, cycloalkyl, cyano, fluoro, chloro, bromo, iodo,NH₂, NHR, NR₂, —OM, OR, and —COOQ. Also, at least one G group is asupport, M is chosen from hydrogen, alkyl, haloalkyl, cycloalkyl,phenyl, and substituted phenyl, and Q is chosen from hydrogen and alkyl.E includes a group chosen from sulfur, sulfoxide, sulfone, selenium,selenoxide, and selenone. T, X, and Z are groups each independentlychosen from ¹H, ²H, a C₁-C₄ alkyl, fluoro, chloro, bromo, iodo, amino,NHR, NR₂, and OR. R is chosen from a C₁-C₄ alkyl, chloro, bromo, amino,a monocyclic aryl, substituted monocyclic aryl, bicyclic aryl, andsubstituted bicyclic aryl. At least one of C, T, X, and Z comprises astable isotope, wherein the stable isotope of C is ¹³C and wherein thestable isotope of T, X, Z is chosen from ¹³C or ²H.

Another embodiment composition having a support is of the formula

and another is its structural isomer, which is of the formula

wherein each G group is independently chosen from a support, hydrogen, aC₁-C₄ alkyl, haloalkyl, cycloalkyl, cyano, fluoro, chloro, bromo, iodo,NH₂, NHR, NR₂, —OM, OR, and —COOQ. Also, at least one G group is asupport, M is chosen from hydrogen, alkyl, haloalkyl, cycloalkyl,phenyl, and substituted phenyl, and Q is chosen from hydrogen and alkyl.E includes a group chosen from sulfur, sulfoxide, sulfone, selenium,selenoxide, and selenone. T, X, and Z are groups each independentlychosen from ¹H, ²H, a C₁-C₄ alkyl, fluoro, chloro, bromo, iodo, amino,NHR, NR₂, and OR. R is chosen from a C₁-C₄ alkyl, chloro, bromo, amino,a monocyclic aryl, substituted monocyclic aryl, bicyclic aryl, andsubstituted bicyclic aryl. At least one of C, T, X, and Z comprises astable isotope, wherein the stable isotope of C is ¹³C and wherein thestable isotope of T, X, Z is chosen from ¹³C or ²H.

Some non-limiting embodiment sulfide-containing compositions include thefollowing, wherein a solid phase support represented by

Embodiment compositions may also include a solid phase support attachedby oxygen to isotopically a labeled methyl aryl sulfoxide. The sulfoxidecan generally be prepared by oxidation of the corresponding sulfide(see, for example: Rayner, Contemporary Organic Synthesis, vol. 1,(1994), pp. 191-203; Rayner, Contemporary Organic Synthesis, vol. 2,(1995), pp. 409-440; Rayner, Contemporary Organic Synthesis, vol. 3,(1996), pp. 499-533; and Baird et al., J. Chem. Soc., Perkin Trans. 1,vol. 12, (1998), pp. 1973-2003, all incorporated by reference). Somenon-limiting embodiments include those of the formula

Other embodiment compositions include a support attached to isotopicallylabeled methyl aryl sulfone groups. In at least some cases, the sulfonemay be prepared by oxidation of the corresponding sulfide or sulfoxide(see, for example: Rayner, Contemporary Organic Synthesis, vol. 1,(1994), pp. 191-203; Rayner, Contemporary Organic Synthesis, vol. 2,(1995), pp. 409-440; Rayner, Contemporary Organic Synthesis, vol. 3,(1996), pp. 499-533; and Baird et al., J. Chem. Soc., Perkin Trans. 1,vol. 12, (1998), pp. 1973-2003). Some non-limiting embodiments includethose of the formula

In other embodiment compositions, a solid phase support is attached toisotopically labeled methyl aryl selenide groups. Some non-limitingembodiments include those of the formula

In other embodiment compositions, a solid phase support is attached toisotopically labeled methyl aryl selenoxide groups. Some non-limitingexamples of this composition include those of the formula

In other embodiment compositions, a solid phase support is attached toisotopically labeled methyl aryl selenone groups. Some non-limitingexamples of this composition include those of the formula

Other embodiment compositions include a solid phase support attached toisotopically labeled methyl aryl polysulfide groups. Some non-limitingexamples of this composition include those of the formula

Other embodiment compositions include a solid phase support attached toisotopically labeled methyl aryl polyselenide groups. Some embodimentsinclude those of the formula

An embodiment composition that includes an affinity tag is of theformula

wherein T, X, and Z are groups each independently chosen from ¹H, ²H, aC₁-C₄ alkyl, fluoro, chloro, bromo, iodo, amino, NHR, NR₂, and OR;wherein R is chosen from a C₁-C₄ alkyl, chloro, bromo, amino, amonocyclic aryl, substituted monocyclic aryl, bicyclic aryl, andsubstituted bicyclic aryl; wherein R_(f) is a fluorous group; whereineach J is independently selected from hydrogen and alkyl, wherein m is2, 3, 4, 5, or 6; wherein at least one of C, T, X, and Z comprises astable isotope, wherein the stable isotope of C is ¹³C and wherein thestable isotope of T, X, Z comprises ¹³C or ²H. In the above formula,R_(f)—(CJ₂)_(m)- is exemplary of an affinity tag. Embodiment affinitytags are linear or branched fluorine-containing hydrocarbon groups. Somenon-limiting affinity tag embodiments include those of the formulaC_(n)F_((2n+1))(CR₂)_(m)—, or of the formula C_(n)F_((2n−1))(CR₂)_(m)—,or of the formula C_(n)F_((2n−3))(CR₂)_(m)—, where R is independentlyselected from hydrogen or an alkyl group, wherein n is 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, or 18, and wherein m is 2, 3, 4, 5, or6. Some non-limiting examples of alkyl groups include methyl, ethyl,propyl, isopropyl, butyl, 2-butyl, tert-butyl. Some non-limitingexamples of affinity tags of the generic formulaC_(n)F_((2n+1))(CR₂)_(m)— include C₆F₁₃(CH₂)₃—, C₆F₁₃(CH₂)₂C(CH₃)₂)—,C₈F₁₇(CH₂)₃—, C₈F₁₇(CH₂)₂C(CH₃)₂)—, and C₁₁F₂₁(CH₂)₃—. A non-limitingexample of an affinity tag of the generic formulaC_(n)F_((2n−1))(CR₂)_(m)— is CF₃CF₂(CF)₂(CF₂)₄(CH₂)₂C(CH₃)₂—. Anon-limiting example of affinity tags of the generic formulaC_(n)F_((2n−3))(CR₂)_(m)— is CF₃CF₂CC(CF₂)₄(CH₂)₂C(CH₃)₂—.

The following formulas illustrate some non-limiting embodiments ofisotopically enriched compounds with affinity tags:

The following non-limiting EXAMPLES show a few embodiment preparations.These EXAMPLES are intended to be illustrative only because numerousmodifications and variations will be apparent to those skilled in theart. Some of the EXAMPLES employ solid supports. Others employ affinitytags. Some of the materials used in the preparations were obtained fromthe ALDRICH CHEMICAL COMPANY in reagent quality and were used withoutfurther purification. Resin bound thiophenol (100-200 mesh, 1-1.5millimoles/g, 1% cross-linked with divinylbenzene (DVB)) was obtainedfrom the ALDRICH CHEMICAL COMPANY. Fluorous thiophenol(4-[3-(Perfluorooctyl)-propyl-1-oxy]thiophenol, 99+%) and FLUOROFLASH®were obtained from FLUOROUS TECHNOLOGIES INC. NMR spectra were obtainedusing a BRUKER DRX 300 MHz NMR spectrometer and a tunable broadbandprobe. ¹H and ¹³C spectra were referenced to the tetramethylsilane (TMS)signal at 0.00 ppm through the NMR spectrometer's lock frequency. NMRsamples were dissolved in CDCl₃ for those compounds soluble in organicsolvents, d₆ benzene or expanded with CD₂Cl₂ for solid supportedcompounds. Elemental analyses were performed using a THERMO FINNIGANFLASH 1112 series elemental analyzer. Round bottom flasks were driedwith a propane torch under vacuum and cooled under argon. Reactions wereperformed under a positive pressure of argon, or sealed under argon whenusing a Falcon tube.

EXAMPLE 1

Preparation of resin bound [¹³C]methyl-(4-phenol)-sulfide (2). Compound2 was prepared as follows: Resin bound 4-thiophenol (1) (250 milligrams,about 0.312 millimoles) was added to a flame-dried round bottom flaskunder an argon atmosphere. Tetrahydrofuran (THF, 10 milliliters) and DBU(0.19 milliliters, 1.2 millimoles) were also added to the flask. Themixture was stirred at room temperature for 5 minutes, and then ¹³CH₃I(0.059 milliliters, 0.63 millimoles) was added, and the resultingmixture was stirred overnight. The resulting resin washed withN-methyl-2-pyrrolidone (NMP, 3×10 milliliters) and CH₂Cl₂ (5×10milliliters). Analysis of the resin by NMR indicated the presence ofunreacted 1. The resin was recombined with reagents with the exceptionthat the amount of ¹³CH₃I was halved. The mixture was stirred overnight.The washing steps were repeated, and the product resin was dried under avacuum. Average loading theoretical=1.23 mmol/g, 3.94% S. ElementalAnalysis: % C=87.25; % H=7.58; % S=3.45. Loading based on EA found (%S): 1.08 mmol/g (88% yield) Based on the amount of ¹³CH₃I consumed, theyield of 2 was 29% (unoptimized, excess DBU consumes ¹³CH₃I).

EXAMPLE 2

Preparation of resin bound [¹³C]methyl-(4-phenol)-sulfoxide (3). Resin 3was prepared as follows: Resin bound [¹³C]methyl-(4-phenol)-sulfide (2)(200 milligrams, about 0.26 millimoles) prepared according to EXAMPLE 1,was added to a clean Falcon tube, and then CH₂Cl₂ (9 milliliters),methanol (1 milliliter) and hydrogen peroxide (0.059 milliliters, 0.52millimoles) were added and the tube was sealed. The contents were mixedovernight at room temperature. Afterward, the resin washed with methanol(3×10 milliliters), NMP (3×10 milliliters), and CH₂Cl₂ (5×10milliliters). NMR analysis showed that the product included about a 1:1mixture of 2 and 3. The product resin was combined with reactants, andthe mixture was stirred overnight. After the washing steps, analysisshowed that the reaction was about 90% complete. This product resin wascombined with reactants and the mixture was stirred overnight again.After the washing steps, an NMR analysis showed that the reaction hadgone to completion, yielding about 195 milligrams of 3. Average loadingtheoretical (100% yield for two steps): 1.20 mmol/g, 3.84% S. Elementalanalysis: % C=85.15; % H=7.35; % S=3.75. Loading based on EA found (%S): 1.17 mmol/g (98% for two steps).

EXAMPLE 3

Preparation of resin bound [¹³C]methyl-(4-phenol)-sulfone (4). Resin 4was prepared as follows: Resin bound [¹³C]methyl-(4-phenol)-sulfide (2)(100 milligrams, about 0.13 millimoles) prepared according to EXAMPLE 1,and N-methylpyrrolidone (NMP, 10 milliliters), were added to a cleanFalcon tube. OXONE® (481 milligrams, 0.78 millimoles) was added, thetube was sealed, and the contents were mixed overnight at roomtemperature. Afterward, the product resin washed with methanol (3×10milliliters), NMP (3×10 milliliters), and CH₂Cl₂ (5×10 milliliters).After drying under vacuum, an NMR spectrum of the product showedcomplete conversion to resin 4. The yield of 4 was 101 milligrams.Average loading theoretical (100% yield for two steps): 1.18 mmol/g,3.79% S. Elemental analysis: % C=81.77; % H=7.04; % S=4.48. Loadingbased on EA found (% S): 1.39 mmol/g.

EXAMPLE 4

Preparation of resin bound [¹³C]chloromethyl-(4-phenol)-sulfide (5).Resin 5 was prepared as follows: Resin bound[¹³C]methyl-(4-phenol)-sulfide (2, 105 milligrams, about 0.13millimoles) prepared according to EXAMPLE 1, CH₂Cl₂ ₍10 milliliters),and N-chlorosuccinimide (NCS, 10 milligrams, 0.075 millimoles) wereadded to a clean Falcon tube. After mixing the contents overnight atroom temperature, the resin washed with CH₂Cl₂ (5×10 milliliters). AnNMR spectrum of the product resin showed that the product resin includedabout a 1:1 mixture of 2 and 5. The product resin and reactants werecombined (using a smaller amount of NCS (7 milligrams, 0.052millimoles)). After stirring for about 2 hours, the resin washed asbefore. An NMR spectrum of this product resin showed that the reactionwas about 90% complete. This product resin was combined with reactantsusing an even smaller amount of NCS (4 milligrams, 0.03 millimoles)).The mixture was stirred for about 2 hours. Afterward, the product resinwashed as before. An NMR spectrum of the product resin showed that thereaction had gone to completion. Yield: 105 milligrams of 5. Theoreticalaverage loading: 1.18 mmol/g, 3.78% S. EA found: 68.01% C; 5.91% H;4.22% S. Calculated loading based on found % S: 1.32 mmol/g.

EXAMPLE 5

Preparation of resin bound [¹³C]trichloromethyl-(4-phenol)sulfide (6).Resin 10 was prepared as follows: Resin bound[¹³C]methyl-(4-phenol)-sulfide (2, 200 milligrams, about 0.26millimoles) prepared according to EXAMPLE 1, CH₂Cl₂ (15 milliliters),and N-chlorosuccinimide (NCS, 105 milligrams, 0.78 millimoles) wereadded to a clean Falcon tube. The contents were mixed for two days atroom temperature. The product resin washed with CH₂Cl₂ (5×10milliliters). An NMR spectrum of the resin showed that the reaction hadgone to completion. Yield: 201 milligrams of 6. Theoretical averageloading: 1.09 mmol/g, 3.49% S. EA found: 58.01% C; 4.85% H; 3.79% S.Calculated loading based on found % S: 1.18 mmol/g.

EXAMPLE 6

Preparation of resin bound (4-phenolsulfanyl)-[¹³C₂]acetic acid (7).Resin 7 was prepared as: resin bound 4-thiophenol (1, 200 milligrams,about 0.25 millimoles), [¹³C₂]bromoacetic acid (50 milligrams, 0.3millimoles), NaHCO₃ (100 milligrams, 100 milligrams, 1.2 millimoles),and NMP were added to a clean Falcon tube. The tube was sealed and thecontents were mixed overnight at room temperature. Afterward, the resinwashed with water (3×10 milliliters), methanol (2×10 milliliters), andCH₂Cl₂ (5×10 milliliters). After drying under vacuum, an NMR spectrum ofthe resin indicated good inclusion of the labeled compound into theresin. Theoretical average loading: 1.16 mmol/g, 3.71% S. EA found:81.05% C; 6.91% H; 3.81% S. Calculated loading based on found % S: 1.19mmol/g.

EXAMPLE 7

Preparation of resin bound(4-phenolsulfanyl)-(N,N-dimethyl)-[¹³C₂]acetamide (8). Resin 8 wasprepared as follows: resin bound (4-phenolsulfanyl)-[¹³C₂]acetic acid(7, 200 milligrams, about 1.23 millimoles) prepared according to EXAMPLE6 was added to a clean Falcon tube along with 1-hydroxybenzotriazole(HOBT, 0.5 M in NMP, 0.54 milliliters, 0.27 millimoles), andN,N-diisopropylcarbodiimide (DIC, 42 μl, 0.27 millimoles). Dimethylamine(2 M in THF, 0.27 milliliters, 0.54 millimoles) was then added alongwith CH₂Cl₂ (10 milliliters). The tube was sealed and the contents weremixed overnight at room temperature. The resin washed with CH₂Cl₂ (5×10milliliters) and dried under vacuum. An NMR spectrum of the resin showedthat the reaction was not complete. The product resin from theincomplete reaction was combined with fresh reactants and mixed at roomtemperature overnight. Washing was repeated as before, and the NMRspectrum of the resin indicated that the reaction was about 90%complete. This resin was combined with reagents and mixed overnight atroom temperature. After washing, the NMR spectrum of the resin indicatedthat the reaction was complete. Theoretical average loading: 1.12mmol/g, 3.58% S. EA found: 79.16% C; 6.97% H; 3.24% S. Calculatedloading based on found % S: 1.01 mmol/g (˜91% for two steps).

EXAMPLE 8

Preparation of resin bound(4-phenolsulfanyl)-(N,N-dimethyl)-[¹³C₂]dichloroacetamide (9). Resin 9was prepared as follows: resin bound(4-phenolsulfanyl)-(N,N-dimethyl)-[¹³C₂]acetamide (8, 400 milligrams,about 0.45 millimoles) prepared according to EXAMPLE 7, and CH₂Cl₂ (15milliliters) were added to a clean Falcon tube. SO₂Cl₂ (0.11milliliters, 1.35 millimoles) was added, the tube was sealed, and thecontents were mixed at room temperature for about 2 hours. Afterward,the resin washed with CH₂Cl₂ (5×10 milliliters) and dried under vacuum.An NMR spectrum of the resin indicated that the reaction was complete.Theoretical average loading: 1.04 mmol/g, 3.34% S. EA found: 68.18% C;5.67% H; 3.42% S. Calculated loading based on found % S: 1.06 mmol/g.

EXAMPLE 9

Preparation of N,N-dimethyl-[¹³C₂]oxalamic acid ethyl ester (10).Compound 10 was prepared as follows: resin bound(4-phenolsulfanyl)-(N,N-dimethyl)-[¹³C₂]dichloroacetamide (9, 400milligrams, about 0.42 millimoles), water (0.25 milliliters), andethanol (15 milliliters) were added to a round bottom flask. The mixturewas heated to a temperature of about 80 degrees Celsius overnight. Afterfiltering away the resin, the filtrate was evaporated to give a yellowoil (57 milligrams, essentially quantitative yield). An NMR spectrum ofthe oil indicated that the oil was 10 in high purity.

EXAMPLE 10

Preparation of [¹³C]methyl sulfide, 4-[3-(C₈F₁₇)C₃H₆-1-O]C₆H₄S¹³CH₃(12). Compound 12 was prepared as follows:4-[3-perfluorooctyl)-propyl-1-oxy]thiophenol (11, 500 milligrams, 0.85millimoles) and NaOH (100 milligrams, 2.6 millimoles) were added underan argon atmosphere to a flame dried round bottom flask. Benzene (7.5milliliters) was then added, followed by water (0.85 milliliters). Afterstirring at room temperature for about five minutes, ¹³CH₃I (0.12milliliters, 1.28 millimoles) was added and the reaction was monitoredby NMR spectroscopy. After about two hours, the signal due to thestarting material ¹³CH₃I had an intensity that was about equal to theintensity of the signal due to the ¹³C of product compound (12). Afterabout twenty-four hours, only minor intensity changes corresponding toslight evaporation of the ¹³CH₃I were observed. The reaction mixture wasdiluted with water and the aqueous layer was extracted with CH₂Cl₂. Theorganic portion was dried using Na₂SO₄, filtered, and evaporated to givea white powder. An NMR spectrum of the product showed only small amountsof impurities. The material was purified by preparative thin layerchromatography (12% ethyl acetate in hexanes) to give 492 milligrams(96% yield, 64% based on ¹³CH₃I) of 12 as a white powder.

EXAMPLE 11

Preparation of [¹³C]methyl sulfide, 4-[3-(C₈F₁₇)C₃H₆-1-O]C₆H₄S¹³CH₃(12). Compound 12 was prepared as follows:4-[3-perfluorooctyl)-propyl-1-oxy]thiophenol (11, 100 milligrams, 0.17millimoles) was combined with benzene (3 milliliters),1,8-diazabicyclo[5.4.0.]undec-7-ene (DBU, 0.101 milliliters, 0.68millimoles) and ¹³CH₃I (0.032 milliliters, 0.34 millimoles) under anargon atmosphere at room temperature. After about one hour, no ¹³CH₃Iwas visible by ¹³C NMR spectroscopy. The reaction mixture was dilutedwith water and the aqueous layer was extracted with CH₂Cl₂. The organicportion was dried over Na₂SO₄, filtered, and evaporated to give a whitepowder. The crude material was purified by preparative thin layerchromatography (12% ethyl acetate in hexanes) to give 86 milligrams (85%yield) of 12 as a white powder.

EXAMPLE 12

Preparation of [¹³C]methyl sulfoxide, 4-[3-(C₈F₁₇)C₃H₆-1-O]C₆H₄SO¹³CH₃(13). Compound 13 was prepared as follows: A solution of [¹³C]methylsulfide, 4-[3-(C₈F₁₇)C₃H₆-1-O]C₆H₄S¹³CH₃ (12, 150 milligrams, 0.25millimoles) in benzene (2 milliliters) was prepared and then added to asolution of NalO₄ (53 milligrams, 0.25 millimoles) in methanol (4milliliters). The reaction mixture was stirred at room temperature andmonitored by NMR spectroscopy. After about 48 hours, only trace amountsof compound 12 were visible by ¹³C NMR. The mixture was diluted withwater and extracted with CH₂Cl₂. The organic portion was dried overNa₂SO₄, filtered, and evaporated to give a white powder. Purification bypreparative thin layer chromatography (1:1 ethyl acetate:hexanes) gave144 milligrams (93% yield) of 13 as a white powder.

EXAMPLE 13

Preparation of [¹³C]methyl sulfone, 4-[3-(C₈F₁₇)C₃H₆-1-O]C₆H₄SO₂ ¹³CH₃(14). Compound 14 was prepared as follows: A solution of [¹³C]methylsulfide, 4-[3-(C₈F₁₇)C₃H₆-1-O]C₆H₄S¹³CH₃ (12, 150 milligrams, 0.25millimoles) in a 1:1 solvent mixture of ethyl acetate:ethanol (3milliliters) was prepared. The solution was added to a solution ofOXONE™ (460 milligrams, 0.75 millimoles) in water (13 milliliters). Themixture was stirred at room temperature and monitored by thin layerchromatography (1:1 ethyl acetate:hexanes) and by NMR spectroscopy. Thereaction was quenched after about 48 hours by dilution with water. Theorganic portion was extracted with CH₂Cl₂, dried using Na₂SO₄, filtered,and evaporated to give a white powder. Purification by preparative thinlayer chromatography (1:1 ethyl acetate:hexanes) yielded 143 milligrams(91% yield) of 14 as a white powder.

EXAMPLE 14

Preparation of Perfluorooctyl-propyl-(4-phenolsulfanyl)-[¹³C₂]aceticacid (15). Compound 15 was prepared as follows: A clear solution ofcompound 11 (500 milligrams, 0.85 millimoles) in benzene (6 milliliters)was prepared under argon. A solution of sodium hydroxide (100milligrams, 2.6 millimoles) in water (0.8 milliliters) was also preparedand added with stirring to the solution of compound 11, after which theclear solution turned white and became chunky and frothy. A solution ofbromoacetic acid [¹³C₂] in benzene (2 milliliters) was also prepared andadded to the white mixture. The resulting mixture was stirred to 1 hour,after which it became a uniform white/cream colored suspension. Themixture was stirred an additional 24 hours, then quenched with saturatedNH₄Cl. After rinsing the aqueous layer with CH₂Cl₂, the aqueous layerwas acidified with 6 N HCl to pH 2. Extraction with CH₂Cl₂ followed bydrying (Na₂SO₄) and evaporation of the combined organics gave compound15 (426 milligrams, 78% yield) in good purity as a white powder. Theproduct was used without further purification in subsequent reactions.Elemental analysis calculated: 35.61% C; 2.03% H; 4.96% S. Found: 34.97%C; 1.96% H; 4.16% S.

EXAMPLE 15

Preparation of(Perfluorooctyl)-propyl-(4-phenolsulfanyl)-(N,N-dimethyl)-[¹³C₂]acetamide(16). Compound 16 was prepared as follows: A solution of compound 15 in(10 milliliters) was prepared. A 0.5 M (molar) solution of1-hydroxybenzotriazole (HOBT, 0.4 milliliters, 0.21 millimoles) inN-methylpyrrolidone was added, followed by addition ofdiisopropylcarbodiimide (0.033 milliliters, 0.21 millimoles). Theresulting mixture was stirred at room temperature under argon. Fiveminutes later, a 2 M solution of HN(CH₃)₂ (0.2 milliliters, 0.42millimoles) in tetrahydrofuran (THF) was added and the reaction mixturewas stirred overnight. After NMR analysis confirmed the reaction wascomplete, the solvent was evaporated and the residue was dissolved in aminimum amount of N,N-dimethylformamide (DMF). The resulting mixture waseluted through a FLUOROFLASH® SPE cartridge, using 80:20 methanol:H₂O towash and 100% methanol to elute the product. After evaporation of theproduct fraction, compound 16 (113 milligrams, 95% yield) was obtainedas a white powder. Elemental analysis calculated: 2.08% N; 37.75% C;2.69% H; 4.67% S. Found: 2.32% N; 36.69% C; 2.96% H; 2.75% S.

EXAMPLE 16

Preparation of N,N-Dimethyl-[¹³C₂]oxalamic acid ethyl ester (17).Compound 17 was prepared as follows: A solution of compound 16 (375milligrams, 0.56 millimoles) in CH₂Cl₂ (15 milliliters) was preparedunder argon. The solution was chilled to zero degrees Celsius and SO₂Cl₂(0.14 milliliters, 1.7 millimoles) was added. The mixture was stirred atzero degrees Celsius for 3 hours. After NMR verification of reactioncompletion, the solvent was evaporated and the residue was taken up inethanol (9.5 milliliters) and water (0.5 milliliters). The mixture washeated to 70 degrees Celsius, during which the white solid dissolved.The mixture was heated at this temperature overnight. Afterward, themixture was cooled, and diluted with water, and eluted through aFLUOROFLASH® SPE cartridge, using 80:20 methanol:H₂O to elute the amideester product and 100% methanol to elute the fluorous supported thiol.NMR analysis was positive for pure compound 17 (76 milligrams, 93%yield), as well as thiol (303 milligrams, 92% recovery). The efficacy ofthe thiol was tested on a subsequent reaction that gave an additionproduct in better than 85% yield.

In summary, isotopically labeled compounds are prepared usingcompositions having solid phase supports or affinity tags. Chemicaldetachment of the support or tag results in a labeled compound. Thereactions can be monitored easily using NMR spectroscopy, and thesupport can be regenerated.

The foregoing description of the invention has been presented forpurposes of illustration and description and is not intended to beexhaustive or to limit the invention to the precise form disclosed, andobviously many modifications and variations are possible in light of theabove teaching.

The embodiments were chosen and described in order to best explain theprinciples of the invention and its practical application to therebyenable others skilled in the art to best utilize the invention invarious embodiments and with various modifications as are suited to theparticular use contemplated. It is intended that the scope of theinvention be defined by the claims appended hereto.

1. A composition comprised of the formulaA-D-E-C(TXZ) wherein A comprises a support or an affinity tag; wherein Dcomprises aryl; wherein E comprises sulfur, sulfoxide, sulfone,selenium, selenoxide, or selenone; wherein T, X, and Z comprise groupseach independently chosen from ¹H, ²H, a C₁-C₄ alkyl, aryl, fluoro,chloro, bromo, iodo, amino, NHR, NR₂, and OR wherein R compriseshydrogen, C₁-C₄ alkyl, cycloalkyl, haloalkyl, aryl, chloro, bromo,amino, and aryl; and wherein at least one of C, T, X, and Z comprises astable isotope, wherein the stable isotope of C is ¹³C and wherein thestable isotope of T, X, Z comprises ¹³C or ²H.
 2. The composition ofclaim 1, wherein A comprises an affinity tag of the formulaC_(n)F_((2n+1))(CJ₂)_(m)-, or of the formula C_(n)F_((2n−1))(CJ₂)_(m)-,or of the formula C_(n)F_((2n−3))(CJ₂)_(m)-, wherein J is independentlyselected from hydrogen and alkyl, wherein n is 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, or 18, and wherein m is 2, 3, 4, 5, or
 6. 3. Thecomposition of claim 2, wherein each J is independently selected fromhydrogen, methyl, ethyl, 1-propyl, 2-propyl, butyl, 1-butyl, 2-butyl,and tert-butyl.
 4. The composition of claim 1, wherein A comprises asolid support chosen from a polymer support, a resin support, a metalsupport, a nanoparticle support, a magnetic bead support, a silicasupport, a silicon support, a glass support, a ceramic support, and acore-shell compound support.
 5. The composition of claim 1, wherein Acomprises an affinity tag of the formula (C₈F₁₇)(CH₂)₂(CR₁₂)₃— whereinR′ is independently selected from hydrogen and methyl.
 6. Thecomposition of claim 1, wherein group D comprises an aryl group having6-10 ring atoms.
 7. The composition of clam 1, wherein D comprises anoxygen atom attached to A.
 8. The composition of claim 1, wherein Dcomprises monocyclic aryl, monocyclic aryloxy, functionalized monocyclicaryloxy, bicyclic aryl, bicyclic aryloxy, functionalized bicyclicaryloxy, wherein functionalized monocyclic aryl, functionalizedmonocyclic aryloxy, functionalized bicyclic aryl, and functionalizedbicyclic aryloxy comprise a substituent chosen from alkyl, haloalkyl,cycloalkyl, halo, nitro, cyano, —OM, and —COOQ, wherein M is chosen fromhydrogen, alkyl, haloalkyl, cycloalkyl, phenyl, and substituted phenyl,and wherein Q is chosen from hydrogen and alkyl.
 9. The composition ofclaim 1, wherein E is sulfur, sulfoxide, or sulfone; wherein C is ¹³C;and wherein at least one of T, X, and Z is ²H.
 10. The composition ofclaim 1, wherein haloalkyl comprises fluoroalkyl, bromoalkyl,chloroalkyl, and iodoalkyl.
 11. The composition of claim 1, wherein T,X, and Z comprise monocyclic aryl, monocyclic aryloxy, functionalizedmonocyclic aryloxy, bicyclic aryl, bicyclic aryloxy, functionalizedbicyclic aryloxy, wherein functionalized monocyclic aryl, functionalizedmonocyclic aryloxy, functionalized bicyclic aryl, and functionalizedbicyclic aryloxy comprise a substituent chosen from alkyl, haloalkyl,cycloalkyl, halo, nitro, cyano, —OM, and —COOQ, wherein M is chosen fromhydrogen, alkyl, haloalkyl, cycloalkyl, phenyl, and substituted phenyl,and wherein Q is chosen from hydrogen and alkyl.
 12. A compositioncomprised of the formula

or comprised of the formula

or comprised of the formula

or comprised of the formula

wherein each G is independently chosen from a support, hydrogen, a C₁-C₄alkyl, haloalkyl, cycloalkyl, cyano, fluoro, chloro, bromo, iodo, NH₂,NHR, NR₂, —OM, OR, and —COOQ; wherein at least one G is a support;wherein M is chosen from hydrogen, alkyl, haloalkyl, cycloalkyl, phenyl,and substituted phenyl; wherein Q is chosen from hydrogen and alkyl;wherein E comprises sulfur, sulfoxide, sulfone, selenium, selenoxide,and selenone; wherein T, X, and Z are groups each independently chosenfrom ¹H, ²H, a C₁-C₄ alkyl, fluoro, chloro, bromo, iodo, amino, NHR,NR₂, and OR wherein R is chosen from a C₁-C₄ alkyl, chloro, bromo,amino, a monocyclic aryl, substituted monocyclic aryl, bicyclic aryl,and substituted bicyclic aryl; wherein R_(f) is a fluorous group;wherein each J is independently selected from hydrogen and alkyl,wherein m is 2, 3, 4, 5, or 6; and wherein at least one of C, T, X, andZ comprises a stable isotope, wherein the stable isotope of C is ¹³C andwherein the stable isotope of T, X, Z comprises ¹³C or ²H.
 13. Thecomposition of claim 12, wherein G is a support chosen from a polymersupport, a resin support, a nanoparticle support, a magnetic beadsupport, a silica support, a silicon support, a glass support, a ceramicsupport, or a core-shell compound support.
 14. The composition of claim12, wherein fluorous group R_(f) is comprised of the formula—C_(n)F_((2n+1)), or of the formula —C_(n)F_((2n−1)), or of the formula—C_(n)F_((2n−3)), wherein n is 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, or 18, and wherein m is 2, 3, 4, 5, or
 6. 15. The composition ofclaim 14, wherein each J is independently selected from hydrogen,methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, and tert-butyl.
 16. Amethod for synthesizing an isotopically enriched compound, comprising:forming a composition comprised of the formulaA-D-E-C(TXZ) wherein A comprises a support or an affinity tag; wherein Dcomprises aryl; wherein E comprises sulfur, sulfoxide, sulfone,selenium, selenoxide, or selenone; wherein T, X, and Z comprise groupseach independently chosen from ¹H, ²H, a C₁-C₄ alkyl, fluoro, chloro,bromo, iodo, amino, NHR, NR₂, and OR; wherein R comprises C₁-C₄ alkyl,chloro, bromo, amino, a monocyclic aryl, substituted monocyclic aryl,bicyclic aryl, and substituted bicyclic aryl; and wherein at least oneof C, T, X, and Z groups comprises a stable isotope, wherein the stableisotope of C is ¹³C and wherein the stable isotope of T, X, Z comprises¹³C or ²H; and subjecting the composition to conditions whereby —C(TXZ)detaches from E and becomes part of an isotopically labeled compound.17. The method of claim 16, wherein A comprises an affinity tag of theformula C_(n)F_((2n+1))(CJ₂)_(m)-, or of the formulaC_(n)F_((2n−1))(CJ₂)_(m)-, or of the formula C_(n)F_((2n−3))(CJ₂)_(m)-,wherein R is independently selected from hydrogen and alkyl, wherein nis 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18, and whereinm is 2, 3, 4, 5, or
 6. 18. The method of claim 17, wherein each J isindependently selected from hydrogen, methyl, ethyl, propyl, 2-propyl,butyl, 2-butyl, and tert-butyl.
 19. The method of claim 14, wherein Acomprises a solid support chosen from a polymer support, a resinsupport, a metal support, a nanoparticle support, a magnetic beadsupport, a silica support, a silicon support, a glass support, a ceramicsupport, and a core-shell compound support.
 17. The method of claim 14,wherein group D comprises an aryl group having 6-10 ring atoms.
 18. Themethod of claim 14, wherein D comprises an oxygen atom attached to A.19. The method of claim 14, wherein D comprises monocyclic aryl,monocyclic aryloxy, functionalized monocyclic aryloxy, bicyclic aryl,bicyclic aryloxy, functionalized bicyclic aryloxy, whereinfunctionalized monocyclic aryl, functionalized monocyclic aryloxy,functionalized bicyclic aryl, and functionalized bicyclic aryloxycomprise a substituent chosen from alkyl, haloalkyl, cycloalkyl, halo,nitro, cyano, —OM, and —COOQ, wherein M is chosen from hydrogen, alkyl,haloalkyl, cycloalkyl, phenyl, and substituted phenyl, and wherein Q ischosen from hydrogen and alkyl.
 20. The method of claim 14, wherein E issulfur, sulfoxide, or sulfone; wherein C is ¹³C; and wherein at leastone of T, X, and Z is ²H.
 21. The method of claim 14, wherein haloalkylcomprises fluoroalkyl, bromoalkyl, chloroalkyl, and iodoalkyl.
 22. Themethod of claim 14, wherein T, X, and Z comprise monocyclic aryl,monocyclic aryloxy, functionalized monocyclic aryloxy, bicyclic aryl,bicyclic aryloxy, functionalized bicyclic aryloxy, whereinfunctionalized monocyclic aryl, functionalized monocyclic aryloxy,functionalized bicyclic aryl, and functionalized bicyclic aryloxycomprise a substituent chosen from alkyl, haloalkyl, cycloalkyl, halo,nitro, cyano, —OM, and —COOQ, wherein M is chosen from hydrogen, alkyl,haloalkyl, cycloalkyl, phenyl, and substituted phenyl, and wherein Q ischosen from hydrogen and alkyl.